Edinburgh Research Explorer

Delayed neutrophil apoptosis enhances NET formation in cystic fibrosis

Research output: Contribution to journalArticlepeer-review

  • Kate H Regan
  • Maeve Smith
  • Calum T Robb
  • Annie Mackellar
  • Lily Paemka
  • Brian N McCullagh
  • Dorward David
  • Edward F McKone
  • Gordon Cooke
  • Pradeep K Singh
  • David A Stoltz
  • Paul B McCray

Related Edinburgh Organisations

Open Access permissions



  • Download as Adobe PDF

    Rights statement: This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

    Final published version, 7.87 MB, PDF document

    Licence: Creative Commons: Attribution (CC-BY)

Original languageEnglish
Pages (from-to)134-144
Number of pages11
Issue number2
Early online date15 Sep 2017
Publication statusPublished - Feb 2018


Background: CF lung disease is defined by large numbers of neutrophils and associated damaging products in the airway. Delayed neutrophil apoptosis is described in CF although it is unclear whether this is a primary neutrophil defect or a response to chronic inflammation. Increased levels of neutrophil extracellular traps (NETs) have been measured in CF and we aimed to investigate the causal relationship between these phenomena and their potential to serve as a driver of inflammation. We hypothesized that the delay in apoptosis in CF is a primary defect and preferentially allows CF neutrophils to form NETs, contributing to inflammation.

Methods: Blood neutrophils were isolated from CF patients, CF pigs and appropriate controls. Neutrophils were also obtained from CF patients before and after commencing Ivacaftor. Apoptosis was assessed by morphology and flow cytometry. NET formation was determined by fluorescent microscopy and DNA release assays. NET interaction with macrophages was examined by measuring by cytokine generation by ELISA and qRT-PCR.

Results: CF neutrophils live longer due to decreased apoptosis. This was observed in both CFTR null piglets and CF patients, and furthermore was reversed by ivacaftor (CFTR potentiator) in patients with gating (G551D) mutations. CF neutrophils formed more NETs and this was reversed by cyclin-dependent kinase inhibitor (CDKi) exposure. NETs provided a pro-inflammatory stimulus to macrophages, which was enhanced in CF.

Conclusions: CF neutrophils have a pro-survival phenotype that is associated with an absence of CFTR function and allows increased NET production, which can in turn induce inflammation. Augmenting neutrophil apoptosis in CF may allow more appropriate neutrophil disposal, decreasing NET formation and thus inflammation.

Download statistics

No data available

ID: 42441809